Immune activation induces activation and maturation of dendritic cells. Dendritic cells are a part of the immune system that act as antigen-presenting cells. Dendritic cells process antigen material and present it on their cell surface. The antigen material may be from viruses and bacteria.
Immature dendritic cells become activated after detecting an antigen. The antigen protein is degraded by the dendritic cell and the fragments are presented on the surface of the dendritic cell. After the dendritic call is activated, it migrates to the lymph nodes and displays the antigen to other immune system cells.
Cytokine mixes currently used to activate and mature dendritic cells are sub-optimal. These mixes typically include a combination of one or more of: interleukin-1β (IL-1β), tumor necrosis factor-α (TNFα), interleukin-6 (IL-6), interferon-γ (IFN-γ), type I interferon, lipopolysaccharide (LPS), and prostaglandin E2 (PGE2). In some cases, the cytokine mix matures the dendritic cell, but does not induce the migration of the dendritic cell to the lymphoid organs where T cells are activated. In other cases, the cytokine mix can induce migration (typically by including PGE2), but the mix prevents important actions by the dendritic cell, such as responsiveness to T cell help, or the costimulatory ligand CD40L, and expression of the cytokine IL-12p70, both of which are required for optimal T cell activation and development of immune memory. PGE2 is also known to induce a Th2 immune response, again limiting the effectiveness of the dendritic cells.
Traditional maturation of monocyte derived dendritic cells (MDDC) requires the addition of PGE2. Although PGE2 provides a mature dendritic cell that is able to home to the draining lymph node, there are many problems with this approach. These include making dendritic cells unable to respond to CD40 stimulation and impairing the ability of the dendritic cell to produce IL-12, a key cytokine for Th1 immune activation in the lymph node. (Gilboa, E., DC-based cancer vaccines. J Clin Invest, 117(5): 1195-203 (2007)). Potential methods to mature MDDC without PGE2 include co-transfection of molecular adjuvants such as tumor necrosis family superfamily ligands (TNFSF ligands). (Kornbluth, R. S. and Stone, G. W., Immunostimulatory combinations: designing the next generation of vaccine adjuvants. J Leukoc Biol, 80(5): 1084-102 (2006); Stone, G. W., et al., Multimeric soluble CD40 ligand and GITR ligand as adjuvants for human immunodeficiency virus DNA vaccines. J Virol, 80(4): 1762-72 (2006)).
There is thus a significant need for a method to activate dendritic cells while retaining the ability of the dendritic cells to migrate and the migrated dendritic cells to induce T cell memory by secreting IL-12.